PROJECT SUMMARY PROJECT 1 ? IMPULSIVITY High levels of behavioral impulsivity have been repeatedly linked with both subclinical and clinically-significant patterns of drug misuse, abuse and dependence. As it is often studied in the laboratory, one manifestation of impulsivity is difficulty with suppressing reward-seeking behaviors (impulsive action). Despite the ample evidence that high tendency to engage in impulsive actions segregates with addictions, there is little known about the biological, including genetic, mechanisms that explain this relationship. This project is inspired by data from both animal models and human subjects indicating that trait differences in impulsivity that predate the initiation of drug use (and that likely reflect inherited genetic mechanisms) are susceptibility factors for subsequent drug abuse. The proposed studies involve both recombinant inbred mice (the Collaborative Cross) and a large population of outbred subjects (Diversity Outbred mice), both of which bring exceptional genetic and phenotypic diversity to the analyses. Using integrated systems genetics resources, we will?for the first time?pursue a systematic investigation of the genetic correlations among multiple measures of impulsivity and other addiction-related traits under study in the CSNA's four other scientific projects, including response to novelty and novelty-preference, initial locomotor response to cocaine and locomotor sensitization to repetitive dosing, nicotine reward and conditioning, circadian phenotypes and?a gold standard addiction-relevant behavior?intravenous cocaine self-administration. Expression of genes and gene co-expression networks that are genetically correlated with impulsivity and with cocaine-induced alterations in impulsivity will also be identified. Genome-wide association analyses will identify quantitative trait loci for both impulsivity and for expression traits correlated with impulsivity. Associated alleles will be functionally validated, and new model organisms enabling mechanistic studies of allelic effects on physiology and behavior will be created. These analyses represent the deepest phenotypic and genomic analysis of impulsivity yet conducted and will expose new biological influences on inter-individual differences in addiction liability.